Major Depressive Disorder (MOD) is one of the most prevalent psychiatric problems faced by U.S. adults. Although MOD appears to be highly heritable, genetic association studies for this disorder have been variable and equivocal. Identifying intermediate phenotypes may be crucial for advancing our understanding of MDD. Neurobiological models suggest that genetic variants of the serotonin transporter (5-HTTLPR) play a crucial role within a widely distributed and interconnected system of cortical and subcortical pathways that regulate processing of emotion cues. Some researchers have speculated that serotonergic polymorphisms increase the risk for and maintenance of affective disorders by contributing to altered processing of emotional stimuli. Our primary aim is to use a state-of-the-art eye tracking paradigm to examine whether polymorphisms of the 5-HTTLPR are associated with biased processing of dysphoric emotion cues among adults with MDD. Further, we will also examine whether short 5-HTTLPR allele carriers with no current or past psychopathology also display similar processing biases of dysphoric emotion cues when induced into a transient dysphoric mood. Secondary aims will examine 5-HTTLPR genotype effects for other emotion cue processing biases, such as over-identifying sadness in emotionally ambiguous stimuli, difficulty disengaging attention from dysphoric information, and self-reported tendencies to ruminate about emotional information. Our final aim is to investigate two other genetic polymorphisms (i.e., Catechol-O-methyltransferase [COMT] and tryptophan hydroxylase 2 [TPH2]) that have been associated with increased risk for MDD, impact the function of the corticolimbic emotion circuits, and have a relatively high minor allele frequency. This translational study should thus help to elucidate the mechanisms by which three common genetic polymorphisms contribute to the expression of a critical phenotype in MDD. Thus, the proposed study should advance our knowledge of the etiological and maintenance processes for MDD and provide specific direction for the design of treatment programs for this serious psychiatric problem.